Mycophenolic acid ("MPA") , chemically known as 6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl) -4-methyl-4-hexenoic acid was initially described as a weakly-active antibiotic found in the fermentation broth of Penicillium brevicompactum, having the following structure. ##STR1## MPA and certain related compounds, such as mycophenolate mofetil (the morpholinoethyl ester of MPA, chemically known as morpholinoethyl E-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-m ethyl-4-hexenoate), having the following structure: ##STR2## have more recently been described as having particularly advantageous therapeutic properties, e.g., as immunosuppressant drugs. See, for example, U.S. Pat. Nos. 3,880,995; 4,727,069; 4,753,935; and 4,786,637, all incorporated herein by reference.
MPA and mycophenolate mofetil, notwithstanding the improved oral bioavailability characteristics of the latter, require daily doses on the order of 2.0 to as much as 3.5 or 4.0 grams per day (or even 5.0 grams per day in the case of MPA, for example as described in U.S. Pat. No. 3,880,995) depending upon the patient and the disease state being treated. Using a conventional dosage formulation containing 250 mg in a standard size 1 (0.48 cc volume) capsule, a patient receiving a 3.0 gram daily dose is required to take twelve capsules each day, giving rise to patient convenience and compliance concerns. It has remained desired to provide high dose oral formulations for MPA and mycophenolate mofetil, particularly in view of their relatively high daily doses.
Ranolazine, known chemically (.+-.)N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-1-pi perazine acetamide, is described in U.S. Pat. No. 4,567,264 as having advantageous therapeutic properties, e.g., for cardiovascular disease including arrhythmias, variant and exercise induced angina and myocardial infarction and for treatment of tissues experiencing a physical or chemical insult, including treating cardioplegia, hypoxic and/or reperfusion injury to cardiac or skeletal muscle or brain tissue, and for use in transplants.
The filling of molten or thixotropic liquids and pastes into hard gelatin capsules has been described as a way of reducing the problems of conventional pharmaceutical processing methods, and adaptations of capsule filling machines for this purpose have been described in the literature See, e g., Walker, et al., "The filling of molten and thixotropic formulations into hard gelatin capsules," J.Pharm.Pharmacol., Vol. 32, 389-393 (1980); and McTaggart, et al., "The evaluation of an automatic system for filling liquids into hard gelatin capsules," J. Pharm. Pharmacol., Vol. 36, 119-121 (1984). The advantages of this formulation technology have been described as including "low content uniformity variation, reduced dust generation giving rise to reduced cross contamination hazards, controlled dissolution rate using solid solution or slow release systems, the ability to process low melting point or liquid drugs and the possibility of in-house formulation development and manufacture" (McTaggart, et al., at page 119). Liquid-filled hard-gelatin capsule formulations have been particularly suggested for "drugs that have low melting points, drugs that are low-dosed or that are oxygen- or moisture-labile, and drugs that require bioavailability enhancement" including "the development of sustained-release formulations." Cole, "Liquid Filled Hard Gelatin Capsules," Pharm. Technol., Vol. 13, No. 9, 134-140 at 134 (1989).
More recently, a new aspect of liquid-paste filling was reported "whereby a high fill weight of a low-melting thermostable drug (ibuprofen) can be attained using low levels of excipient whilst preserving the facility to obtain a wide range of drug release rates." Smith, et al., "The filling of molten ibuprofen into hard gelatin capsules," Int. J. Pharm., Vol. 59, 115-119 at 115 (1990). There, ibuprofen (m.p. 77.degree. C.) was heated to 70.degree.-80.degree. C., alone and with a variety of excipients, and filled into a variety of capsule sizes. Maximum approximate fill weights for ibuprofen alone, of 450 mg (size 1), 605 mg (size 0), 680 mg (size 0 elongated), and 825 mg (size 00), were reported.
Mycophenolate mofetil has a melting point of 95.degree. C. MPA has a melting point of 141.degree. C. Ranolazine free base has a melting point of 120.degree. C. None is a low-melting drug that would be considered suitable for hot melt filling, particularly given an upper fill temperature of 80.degree. C., preferably below 60.degree. C., for hard gelatin capsules due to their own melting characteristics. It was surprisingly discovered that mycophenolate mofetil, once heated above its melting point, has the unexpected property of remaining liquid for sustained periods of time after cooling to significantly lower temperatures. Such a considerable delay in solidification even after cooling below melting point (a "supercooling" phenomena) was reported as "a problem" to be overcome in the preparation of medications in the form of pearls (see U.S. Pat. No. 5,188,838).
In the present invention, mycophenolate mofetil's ability to be supercooled has been extended by the application of that discovery to hot melt filling, to produce previously unattainable high dose formulations. It has also been discovered that MPA exhibits the ability to be supercooled, and while the duration is shorter than that measured for mycophenolate mofetil, MPA's supercooling duration is sufficient for producing previously unattainable high dose formulations.